The renal reabsorption of glucose is mediated by two major classes of transporters. Initially, luminal glucose is concentrated in tubules by Na(+)-glucose cotransporters (Na(+)-GLUT). Afterwards, glucose reaches the blood space through facilitative glucose transporters, low-Michaelis constant (Km) GLUT1 and high-Km GLUT2. Hence, the transtubular flux of glucose could be impaired in hyperglycemia because the outwardly directed glucose gradient, from tubule to blood, is potentially lowered. However, in diabetic rats, transtubular glucose flux is not reduced but increased. In this work the molecular mechanism underlying this adaptation was examined. We tested the hypothesis that upregulation of renal tubular high-Km GLUT2 gene may compensate for the decrease in the tubule to blood glucose gradient. In rat tubules, GLUT1 protein and mRNA steady-state levels were reduced, and GLUT2 protein and mRNA levels were increased in rats after 2, 3, and 4 wk of uncontrolled streptozotocin-induced diabetes. These molecular adaptations were associated with augmented facilitative glucose flux. In summary, changes in GLUT1 and GLUT2 gene expression are important to the preservation of renal glucose reabsorption in hyperglycemia.
In the late proximal tubule, glucose reabsorption progressively lowers the concentration of luminal glucose, and concentrative glucose influx increases to ensure complete glucose reabsorption. The change in glucose influx is effected by luminal Na(+)-dependent glucose transporters (Na(+)-GLUT), which exhibit higher Na(+)-to-glucose stoichiometric ratios in the late proximal tubule. In this work, the corresponding changes in the axial distribution of basolateral glucose efflux transporters (GLUTs) were examined. mRNAs encoding high-affinity facilitative basolateral transporter GLUT1, low-affinity GLUT2, and apical Na(+)-GLUT were identified in mixed populations of proximal convoluted and straight tubules. The organization of the cognate proteins was also appraised on Western blots. GLUT1 was present in glomeruli, proximal convoluted, and straight tubules, GLUT2 was only expressed in the proximal convoluted tubule, and Na(+)-GLUT was present in both proximal convoluted and straight segments. GLUT1 and GLUT2 were confined to the basolateral membrane, whereas Na(+)-GLUT was preferentially localized to the brush-border membrane. These data are consistent with the idea that glucose influx in early and late proximal tubule is achieved through Na(+)-GLUT, that GLUT1 and GLUT2 are responsible for glucose efflux in the early proximal tubule, and that in the late proximal tubule, where transcellular glucose flux is lower, only GLUT1 mediates glucose efflux.
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